Novel compounds

Abstract

The invention relates to compounds of Formula (I) and their use in therapy, for example in the treatment of mycobacterial infections or in the treatment of diseases caused by mycobacterium, such as tuberculosis.

1 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; m is 0 or 1; 
         R 1  is H or F; and 
         R 2  is pyridyl optionally substituted by one or two substituents independently selected from fluoro, chloro, bromo, cyano, methyl optionally substituted by one or more fluoro, and methoxy optionally substituted by one or more fluoro, or 
         R 2  is pyrazinyl optionally substituted at the meta position by a substituent selected from fluoro, chloro, bromo, cyano, methyl optionally substituted by one or more fluoro, and methoxy optionally substituted by one or more fluoro, or 
         R 2  is pyrazinyl optionally substituted at the para position by fluoro or chloro, wherein when R 1  is H, R 2  is substituted, and when m is 0, R 1  is H. 
       
     
     
         2 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein n is 1. 
     
     
         3 . A compound or pharmaceutically acceptable salt thereof according to  claim 1 or claim 2 , wherein m is 1. 
     
     
         4 . A compound or pharmaceutically acceptable salt thereof according to  any one of the preceding claims , wherein R 2  is pyridyl optionally substituted by one or two substituents independently selected from fluoro, chloro, methyl, trifluoromethyl, and methoxy, wherein when the substituent is trifluoromethyl it is attached at the meta position of the pyridine ring; or R 2  is pyrazinyl meta substituted by one or two substituents independently selected from fluoro, chloro and trifluoromethyl; or R 2  is pyrazinyl para substituted by fluoro or chloro. 
     
     
         5 . A compound or pharmaceutically acceptable salt thereof according to  any one of the preceding claims , wherein R 1  is H. 
     
     
         6 . A compound or pharmaceutically acceptable salt thereof according to  any one of the preceding claims , wherein when R 2  is substituted, it is substituted at the meta position. 
     
     
         7 . A compound or pharmaceutically acceptable salt thereof according to  any one of the preceding claims , wherein R 2  is pyridyl substituted by one or two substituents independently selected from fluoro, chloro, methyl, trifluoromethyl, and methoxy, wherein when the substituent is trifluoromethyl it is attached at the meta position of the pyridine ring; or R 2  is pyrazinyl meta substituted by one or two substituents independently selected from fluoro, chloro and trifluoromethyl; or R 2  is pyrazinyl para substituted by fluoro or chloro. 
     
     
         8 . A compound or pharmaceutically acceptable salt thereof according to  claim 5 , wherein R 2  is pyridyl substituted by one substituent selected from fluoro, chloro, bromo, cyano, methyl optionally substituted by one or more fluoro, and methoxy optionally substituted by one or more fluoro. 
     
     
         9 . A compound or pharmaceutically acceptable salt thereof according to  any one of the preceding claims , wherein R 2  is pyridyl substituted by one substituent at the meta position which is selected from chloro, fluoro, methyl, methoxy and trifluoromethyl. 
     
     
         10 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 or claim 9 , wherein R 2  is 4-pyridyl substituted by fluoro, chloro, methyl or trifluoromethyl. 
     
     
         11 . A compound or pharmaceutically acceptable salt thereof according to  claim 10 , wherein R 2  is 4-pyridyl substituted by trifluoromethyl. 
     
     
         12 . A compound or pharmaceutically acceptable salt thereof according to  claim 8 or claim 9 , wherein R 2  is 3-pyridyl substituted by chloro, fluoro, methoxy or trifluoromethyl, wherein when the substituent is trifluoromethyl it is attached to the 5-position of the pyridine ring, and when the substituent is methoxy it is attached to the 6-position of the pyridine ring. 
     
     
         13 . A compound or pharmaceutically acceptable salt thereof according to  claim 2  or any one of  claims 4 to 12 , wherein m is 0. 
     
     
         14 . A compound or pharmaceutically acceptable salt thereof according to  claim 13 , wherein R 2  is 3-pyridyl substituted by one substituent selected from chloro and trifluoromethyl. 
     
     
         15 . A compound or pharmaceutically acceptable salt thereof according to any one of  claims 1 to 3 , wherein R 1  is F. 
     
     
         16 . A compound or pharmaceutically acceptable salt thereof according to  claim 15 , wherein R 2  is 3-pyridyl or 4-pyridyl substituted by one substituent, wherein the substituent is defined as in  claim 1 . 
     
     
         17 . A compound or pharmaceutically acceptable salt thereof according to  claim 15 or claim 16 , wherein R 2  is 3-pyridyl or 4-pyridyl substituted by one substituent, wherein the substituent is chloro, fluoro or trifluoromethyl. 
     
     
         18 . A compound or pharmaceutically acceptable salt thereof according to  any one of the preceding claims  selected from:
 4,4,4-trifluoro-1-[4-fluoro-4-(3-pyridyl)-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-(5-fluoro-3-pyridyl)-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-(6-fluoro-3-pyridyl)-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-[6-(trifluoromethyl)-3-pyridyl]-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-[4-(trifluoromethyl)-2-pyridyl]-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-[5-(trifluoromethyl)-3-pyridyl]-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-[6-(trifluoromethyl)-2-pyridyl]-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-(6-fluoro-2-pyridyl)-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-(6-methoxy-3-pyridyl)-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-[2-(trifluoromethyl)-3-pyridyl]-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-[4-(5-methoxy-3-pyridyl)-1-piperidyl]butan-1-one; 
 1-[4-(3,5-difluoro-2-pyridyl)-1-piperidyl]-4,4,4-trifluoro-butan-1-one; 
 1-[4-(2,6-difluoro-3-pyridyl)-1-piperidyl]-4,4,4-trifluoro-butan-1-one; 
 4,4,4-trifluoro-1-[4-(5-fluoro-2-pyridyl)-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-(4-(2-(trifluoromethyl)pyridin-4-yl)piperidin-1-yl)butan-1-one; 
 4,4,4-trifluoro-1-(4-(2-fluoropyridin-4-yl)piperidin-1-yl)butan-1-one; 
 4,4,4-trifluoro-1-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-1-yl)butan-1-one; 
 4,4,4-trifluoro-1-(4-(2-methylpyridin-4-yl)piperidin-1-yl)butan-1-one; 
 1-(4-(5,6-difluoropyridin-3-yl)piperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 4,4,4-trifluoro-1-(4-(6-(trifluoromethyl)pyrazin-2-yl)piperidin-1-yl)butan-1-one; 
 1-(4-(2-chloropyridin-4-yl)piperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 4,4,4-trifluoro-1-(4-(3-fluoropyridin-4-yl)piperidin-1-yl)butan-1-one; 1-(4-(6-chloropyridin-2-yl)piperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 1-(4-(5-chloropy idin-3-yl)-4-fluoropiperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 1-(4-(5-chloropy idin-3-yl)piperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 1-(4-(5-chloropy idin-3-yl)piperidin-1-yl)-5,5,5-trifluoropentan-1-one; 
 1-(4-(6-chloropy azin-2-yl)piperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 4,4,4-trifluoro-1-4-fluoro-4-(pyridin-2-yl)piperidin-1-yl)butan-1-one; 
 4,4,4-trifluoro-1-4-fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)piperidin-1-yl)butan-1-one; 
 4,4,4-trifluoro-1-4-fluoro-4-(2-(trifluoromethyl)pyridin-4-yl)piperidin-1-yl)butan-1-one; 
 1-(4-(6-chloropy azin-2-yl)-4-fluoropiperidin-1-yl)-4,4,4-trifluorobutan-1-one; 
 4,4,4-trifluoro-1-4-fluoro-4-(2-fluoropyridin-4-yl)piperidin-1-yl)butan-1-one; 
 4,4,4-trifluoro-1-4-fluoro-4-[4-(trifluoromethyl)-2-pyridyl]-1-piperidyl]butan-1-one; 
 4,4,4-trifluoro-1-4-fluoro-4-[4-(trifluoromethyl)-2-pyridyl]-1-piperidyl]butan-1-one; 
 1-(3-(5-chloropy idin-3-yl)pyrrolidin-1-yl)-4,4,4-trifluorobutan-1-one; and 
 1-[4-(2-chloro-4-pyridyl)-4-fluoro-1-piperidyl]-4,4,4-trifluoro-butan-1-one. 
 
     
     
         19 . A compound or pharmaceutically acceptable salt thereof according to  claim 18 , wherein the compound is 4,4,4-trifluoro-1-(4-(2-(trifluoromethyl)pyridin-4-yl)piperidin-1-yl)butan-1-one having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of  claims 1 to 19 , for use in therapy. 
     
     
         21 . A compound of Formula (I) or pharmaceutically acceptable salt thereof as defined in any one of  claims 1 to 19 , for use in the treatment of a mycobacterial infection or for use in the treatment of a disease caused by infection with a  mycobacterium.    
     
     
         22 . A compound or pharmaceutically acceptable salt thereof for use according to  claim 21 , wherein the mycobacterial infection is a  Mycobacterium tuberculosis  infection. 
     
     
         23 . A compound of Formula (I) or pharmaceutically acceptable salt thereof as defined in any one of  claims 1 to 19 , for use in the treatment of tuberculosis. 
     
     
         24 . A method for the treatment of a mycobacterial infection in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, according to any one of  claims 1 to 19 . 
     
     
         25 . A method for the treatment of a disease caused by infection with a  mycobacterium  in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, according to any one of  claims 1 to 19 . 
     
     
         26 . Use of a compound or pharmaceutically acceptable salt thereof according to  claims 1 to 19 , in the manufacture of a medicament for use in the treatment of a mycobacterial infection or a disease caused by infection with a  mycobacterium.    
     
     
         27 . A pharmaceutical composition comprising (a) a compound of Formula (I) or pharmaceutically acceptable salt thereof as defined in any one of  claims 1 to 19 ; and (b) a pharmaceutically acceptable excipient. 
     
     
         28 . A combination of (a) a compound of Formula (I) or pharmaceutically acceptable as defined in any one of  claims 1 to 19 ; and (b) at least one other anti-mycobacterial agent. 
     
     
         29 . A combination according to  claim 28 , wherein the at least one other anti-mycobacterial agent is an anti-tuberculosis agent. 
     
     
         30 . A combination according to  claim 29 , wherein the anti-tuberculosis agent is selected from isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin, rifapentine, clofazimine, ethionamide, prothionamide, isoxyl, thiacetazone, rifabutin, a diarylquinoline such as bedaquiline (TMC207) or TBAJ-587, nitroimidazo-oxazine PA-824, delamanid (OPC-67683), an oxazolidinone such as linezolid, tedizolid, radezolid, sutezolid (PNU-100480), posizolid (AZD-5847) or TBI-223, EMB analogue SQ109, OPC-167832, GSK3036656 (also known as GSK070), GSK2556286, GSK321 1830, a benzothiazinone such as BTZ043 or PBTZ169, an azaindole such as TBA-7371, a dinitrobenzamide, or a beta-lactam such as meropenem, faropenem, ertapenem, tebipenem or beta-lactam combinations such as AUGMENTIN (amoxicillin-clavulanate). 
     
     
         31 . A combination according to any one of  claims 28 to 30 , further comprising an antiviral agent, including an antiretroviral agent. 
     
     
         32 . A combination according to  claim 31 , wherein the antiretroviral agent is selected from zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, GSK1349572, GSK1265744, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, or darunavir.